Comparative molecular dynamics simulations of pathogenic and non-pathogenic huntingtin protein monomers and dimers

Abstract

Polyglutamine expansion at the N-terminus of the huntingtin protein exon 1 (Htt-ex1) is closely associated with a number of neurodegenerative diseases, which result from the aggregation of the increased polyQ repeat. However, the underlying structures and aggregation mechanism are still poorly understood. We performed microsecond-long all-atom molecular dynamics simulations to study the folding and dimerization of Htt-ex1 (about 100 residues) with non-pathogenic and pathogenic polyQ lengths, and uncovered substantial differences. The non-pathogenic monomer adopts a long α-helix that includes most of the polyQ residues, which forms the interaction interface for dimerization, and a PPII-turn-PPII motif in the proline-rich region. In the pathogenic monomer, the polyQ region is disordered, leading to compact structures with many intra-protein interactions and the formation of short β-sheets. Dimerization can proceed via different modes, where those involving the N-terminal headpiece bury more hydrophobic residues and are thus more stable. Moreover, in the pathogenic Htt-ex1 dimers the proline-rich region interacts with the polyQ region, which slows the formation of β-sheets.

Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal

“…The flanking regions and other features of full-length proteins have been shown to modulate both the aggregation and toxicity of polyQ (Adegbuyiro et al, 2017;Arndt et al, 2020;Ceccon et al, 2022;Elena-Real et al, 2023a;Elena-Real et al, 2023b;Hong et al, 2019;Khaled et al, 2023;Kuiper et al, 2017;Lieberman et al, 2019;Silva et al, 2018). The extent to which our findings will translate in these different contexts remains to be determined.…”

A brief history of amyloid aggregation simulations

“…While we have reported here in detail on the simulation of $$$ {\mathrm{A}\upbeta}_{40} $$$ and $$$ {\mathrm{A}\upbeta}_{42} $$$, the corresponding literature on, for example, α‐synuclein is much sparser due to its approximately three times longer sequence (140 amino acid residues). However, recent simulations for this protein 41,147,199 or also for Htt‐ex1 219 show that current computer clusters and MD software allow reasonable simulation of the aggregation of these proteins into oligomers even at the atomistic scale. One question to be answered by future molecular simulations is what the transition pathway from amyloid oligomers to fibrils looks like.…”

“…217,218 The team's most recent work reports dimerization of the huntingtin protein exon 1 (Htt-ex1) with nonpathogenic and pathogenic polyQ lengths relevant to Huntington's disease development. 219 The microsecond-long all-atom MD simulations revealed significant differences in the monomeric and dimeric conformations of these two Htt-ex1 variants. The nonpathogenic monomer adopts a long α-helix that includes most of the polyQ residues that form the interaction interface for dimerization, as well as a PPII-turn PPII motif in the proline-rich region.…”

“…An important aspect of Strodel and her team's work is making direct connections between the Aβ oligomers studied in their simulations and those measured in experiments, including experimental techniques such as sedimentation velocity centrifugation, small‐angle neutron scattering, IM‐MS, and circular dichroism (CD) spectroscopy 217,218 . The team's most recent work reports dimerization of the huntingtin protein exon 1 (Htt‐ex1) with nonpathogenic and pathogenic polyQ lengths relevant to Huntington's disease development 219 . The microsecond‐long all‐atom MD simulations revealed significant differences in the monomeric and dimeric conformations of these two Htt‐ex1 variants.…”

Transient interdomain interactions modulate the monomeric structural ensemble and oligomerization landscape of Huntingtin Exon 1

“…The rapid aggregation kinetics of pathogenic Httex1 fragments limit the ability to achieve a complete atomic-level characterization of the role of flanking domains on structural and oligomerization landscape through experimental approaches alone. Further, conflicting results from previous MD simulation studies (Długosz and Trylska 2011; Kang et al 2017; Khaled et al 2023) due to force field and water model inaccuracies has led to a lack of clarity regarding the precise molecular mechanisms of Httex1 oligomerization and pathogenic aggregation. Our study provides a comprehensive characterization of the structural ensembles of normal and pathogenic N17-polyQ fragments using the AMBER03ws force field which was carefully tuned to achieve balanced secondary structure propensities and protein-water interactions (Best and Mittal 2010; Best et al 2014).…”